Methods and Systems for Locating and Treating Nerves With Cold Therapy

ABSTRACT

The present invention generally relates to improved medical devices, systems, and methods. In many embodiments, devices, systems, and methods for locating and treating a target nerve with cold therapy are provided. For example, a focused cold therapy treatment device may be provided that is adapted to couple with or be fully integrated with a nerve stimulation device such that nerve stimulation and focused cold therapy may be performed concurrently with the cryo-stimulation device. Improvements in nerve localization and targeting may increase treatment accuracy and physician confidence in needle placement during treatment. In turn, such improvements may decrease overall treatment times, the number of repeat treatments, and the re-treatment rate. Further, additional improvements in nerve localization and targeting may reduce the number of applied treatment cycles and may also reduce the number of cartridge changes (when replaceable refrigerant cartridges are used).

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation of U.S. patent applicationSer. No. 15/594,238 filed May 12, 2017 (Allowed); which claims thebenefit of U.S. Provisional Patent Appln No. 62/336,241 filed May 13,2016, the full disclosures which are incorporated herein by reference intheir entirety for all purposes.

BACKGROUND

The present invention generally relates to improved medical devices,systems, and methods. In many embodiments, devices, systems, and methodsfor locating and treating a nerve with cold therapy are provided.

Focused Cold Therapy (“FCT”) may be used to treat nerves, also referredto as cryoneurolysis or cryoneuroablation, to temporarily stop nervesignaling, typically for a set period of time and may be followed by arestoration of nerve function. FCT can be used on motor nerves forvarious cosmetic applications and/or medical conditions, including butnot limited to: movement disorders, muscle spasms, muscle hyperactivityand/or any condition where reduction in muscle movement is desired.Additionally, FCT may be used on sensory nerves to provide temporary orpermanent pain relief by degenerating the nerve and providing aperipheral nerve block. While FCT has many beneficial applications,further improvements in the methods, devices, and systems may be had.

SUMMARY OF THE DISCLOSURE

The present invention generally relates to improved medical devices,systems, and methods. In many embodiments, devices, systems, and methodsfor locating and treating a target nerve with cold therapy are provided.For example, embodiments of the present disclosure may improve nervetargeting during FCT procedures. Improvements in nerve localization andtargeting may increase treatment accuracy and physician confidence inneedle placement during treatment. In turn, such improvements maydecrease overall treatment times, the number of repeat treatments, andthe re-treatment rate. Further, additional improvements in nervelocalization and targeting may reduce the number of applied treatmentcycles and may also reduce the number of cartridge changes (whenreplaceable refrigerant cartridges are used). Accordingly, embodimentsof the present disclosure may provide one or more advantages for FCT byimproving localization and treatment of target nerves.

In some aspects of the present invention, a cryo-stimulation treatmentdevice may be provided. The device may have a needle having a proximalend and a distal end and a length therebetween. The needle may beconfigured to produce a cold zone for focused cold therapy. The needlemay have a cooling center along the length of the needle that isassociated with a center of the cold zone produced by the needle. Thedevice may further include an electrically insulative coating disposedabout the length of the needle. The needle may be electricallyconductive and the proximal end of the needle may be configured tocouple with an electrical nerve stimulation generator that generates anelectrical field about the distal end of the needle for electricallystimulating and locating the target nerve. The cooling center of theneedle may be uninsulated such that an intensity of the electrical fieldmay be co-incident with the center of the cold zone produced by theneedle.

In some embodiments, the electrical nerve stimulation generator orwaveform generator may be coupled with an uninsulated portion of theproximal end of the needle. A handle may be provided that is defined bya housing. The housing may house the electrical nerve stimulationgenerator in certain embodiments.

Optionally, a handle may be provided that is defined by a housing. Thehousing may include an electrical port that electrically couples with anuninsulated portion of the proximal end of the needle. The electricalport may be configured to receive an input associated with theelectrical nerve stimulation generator to electrically couple theelectrical nerve stimulation generator and the needle.

In some embodiments, the needle may be part of a replaceable needleassembly configured for releasable attachment to a handpiece. Thereplaceable needle assembly may include an electrical port thatelectrically couples with an uninsulated portion of the proximal end ofthe needle. The electrical port may be configured to receive an inputassociated with the electrical nerve stimulation generator toelectrically couple the electrical nerve stimulation generator and theneedle.

In some embodiments, the electrically insulated coating comprises afluoropolymer coating. Optionally, the electrically insulated coatingmay be a silicone rubber coating, a parylene coating, a ceramic coating,an epoxy coating, or a polyimide coating.

Optionally, the needle may be a first needle of a needle assembly havingthe first needle and a second needle adjacent the first needle. Thesecond needle may act as an electrical ground during electricalstimulation of the nerve by the first needle.

In further aspects of the present invention, a cryo-stimulationtreatment device may be provided that includes a needle assembly havingone or more treatment needles configured to produce a cold zone forfocused cold therapy of a target nerve. The needle assembly may furtherinclude one or more stimulation needles constructed of electricallyconductive material and being configured to couple with an electricalnerve stimulation generator to produce an electrical field forstimulating the target nerve. In some embodiments, an electricallyinsulating coating may be provided on the one or more stimulationneedles. The one or more stimulation needles may be uninsulated by theelectrically insulating coating at a location of the one or morestimulation needles that is coincident with a center of the cold zoneproduced by the one or more treatment needles.

The one or more stimulation needles may include a center needle. The oneor more treatment needles may include at least two needles that areadjacent the center needle and on opposite sides of the center needle.

Optionally, the one or more treatment needles may include anelectrically insulating coating. At least a distal portion of the one ormore treatment needles may be uninsulated and may act as an electricalground during electrical stimulation of the target nerve by the one ormore stimulation needles, in certain embodiments.

The one or more treatment needles may also be stimulation needlesconstructed of electrically conductive material and may be configured tocouple with an electrical nerve stimulation generator to produce anelectrical field for stimulating the target nerve.

In some embodiments, the device may include a handle defined by ahousing. A distal end of the housing may include an electrical adapterthat electrically couples the needle assembly to the handle. The housingmay house the electrical nerve stimulation generator and connection ofthe needle assembly to the adapter may electrically couple the one ormore stimulation needles with the electrical nerve stimulationgenerator.

In certain embodiments, a handle may be provided that is defined by ahousing. The housing may incorporate an electrical port thatelectrically couples with an uninsulated portion of the one or morestimulation needles. The electrical port may be configured to receive aninput associated with the electrical nerve stimulation generator toelectrically couple the electrical nerve stimulation generator and theone or more stimulation needles.

In some embodiments, the needle assembly may be configured forreleasable attachment to a handpiece. The replaceable needle assemblymay include an electrical port that electrically couples with anuninsulated portion of the one or more stimulating needles. Theelectrical port may be configured to receive an input associated withthe electrical nerve stimulation generator to electrically couple theelectrical nerve stimulation generator and the needle.

In still further embodiments, a method of treating a nerve may beprovided. The method may include inserting one or more needles of aneedle assembly into a tissue of a patient. Thereafter, the nerve may beelectrically stimulated with the needle assembly to localize the nervewithin the tissue. After localizing of the nerve, a focused cold therapymay be delivered to the nerve with the needle assembly. During deliveryof the focused cold therapy, the nerve may be electrically stimulatedwith the needle assembly. An activity of the nerve during the deliveryof the focused cold therapy may be sensed for feedback on the deliveryof the focused cold therapy to the nerve.

In some embodiments, the method may include coupling an input associatedwith an electrical nerve stimulation generator to an electrical port toelectrically couple the electrical nerve stimulation generator and theneedle assembly.

Optionally, coupling the input associated with the electrical nervestimulation generator to the electrical port may comprise coupling theinput associated with the electrical nerve stimulation generator to anelectrical port of the needle assembly.

In certain embodiments, coupling the input associated with theelectrical nerve stimulation generator to the electrical port maycomprise coupling the input associated with the electrical nervestimulation generator to an electrical port disposed on a handlesupporting the needle assembly.

In some embodiments, the method may further include coupling the needleassembly to an adapter of a treatment device handle. Coupling the needleassembly to the adapter of the treatment device handle may electricallycouple an electrical nerve stimulation generator housed in the treatmentdevice handle to one or more needles of the needle assembly.

In some embodiments, the needle assembly may electrically stimulate thenerve and may deliver the focused cold therapy with the same needle.

Optionally, the needle of the needle assembly that electricallystimulates the nerve and delivers the focused cold therapy may have alength between 5-20 cm and a blunt distal tip.

In some embodiments, the needle assembly may electrically stimulate thenerve and deliver the focused cold therapy with different needles of theneedle assembly. The needle assembly may electrically stimulate thenerve and deliver the focused cold therapy with different needles of theneedle assembly. In some embodiments, the needle assembly may include atleast a first needle and a second needle adjacent the first needle. Thefirst needle may electrically stimulate the target nerve and the secondneedle may act as an electrical ground during electrical stimulation ofthe nerve by the first needle. Optionally, the needle assembly mayinclude a center needle and needles adjacent to the center needle. Thetarget nerve may be electrically stimulated by the center needle and thefocused cold therapy may be delivered by the needles adjacent to thecenter needle. In still further embodiments, the focused cold therapymay be delivered by the needles adjacent to the center needle and thecenter needle.

In yet another embodiment, a cooling treatment device may be providedwith a first needle having a proximal end and a distal end and a lengththerebetween and a second needle having a proximal end and a distal endand a length therebetween. The first needle may be electricallyconductive and the proximal end of the first needle may be coupled withan electrical nerve stimulation generator that generates an electricalfield about the distal end of the first needle for nerve stimulation.The second needle may act as an electrical ground during nervestimulation. At least one of the first needle and the second needle maybe configured to produce a cold zone for focused cold therapy.

The terms “invention,” “the invention,” “this invention” and “thepresent invention” used in this patent are intended to refer broadly toall of the subject matter of this patent and the patent claims below.Statements containing these terms should be understood not to limit thesubject matter described herein or to limit the meaning or scope of thepatent claims below. Embodiments of the invention covered by this patentare defined by the claims below, not this summary. This summary is ahigh-level overview of various aspects of the invention and introducessome of the concepts that are further described in the DetailedDescription section below. This summary is not intended to identify keyor essential features of the claimed subject matter, nor is it intendedto be used in isolation to determine the scope of the claimed subjectmatter. The subject matter should be understood by reference toappropriate portions of the entire specification of this patent, any orall drawings and each claim.

The invention will be better understood on reading the followingdescription and examining the figures that accompany it. These figuresare provided by way of illustration only and are in no way limiting onthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Further details, aspects and embodiments of the invention will bedescribed by way of example only and with reference to the drawings. Inthe drawings, like reference numbers are used to identify like orfunctionally similar elements. Elements in the figures are illustratedfor simplicity and clarity and have not necessarily been drawn to scale.

FIG. 1A is a perspective view of a self-contained subdermal cryogenicprobe and system, according to some embodiments of the invention;

FIG. 1B is a partially transparent perspective view of theself-contained probe of FIG. 1A, showing internal components of thecryogenic system and schematically illustrating replacement treatmentneedles for use with the disposable probe according to some embodimentsof the invention;

FIG. 2A schematically illustrates exemplary components that may beincluded in the treatment system;

FIG. 2B is a cross-sectional view of the system of FIG. 1A, according tosome embodiments of the invention;

FIGS. 2C and 2D are cross-sectional views showing exemplary operationalconfigurations of a portion of the system of FIG. 2B;

FIGS. 3A-3E illustrate exemplary embodiments of needle probes, accordingto some embodiments of the invention;

FIGS. 4A-4C illustrate an exemplary method of introducing a cryogenicprobe to a treatment area, according to some embodiments of theinvention;

FIG. 4D illustrates an alternative exemplary embodiment of a sheath,according to some embodiments of the invention;

FIG. 5 illustrates an exemplary insulated cryoprobe, according to someembodiments of the invention;

FIGS. 6-9 illustrate exemplary embodiments of cryofluid delivery tubes,according to some embodiments of the invention;

FIG. 10 illustrates an example of blunt tipped cryoprobe, according tosome embodiments of the invention;

FIGS. 11 and 12 illustrate exemplary actuatable cryoprobes, according tosome embodiments of the invention;

FIG. 13 is a flow chart illustrating an exemplary algorithm for heatingthe needle probe of FIG. 3A, according to some embodiments of theinvention;

FIG. 14 is a flow chart schematically illustrating an exemplary methodfor treatment using the disposable cryogenic probe and system of FIGS.1A and 1B, according to some embodiments of the invention;

FIGS. 15A and 15B illustrate an exemplary system according to someembodiments;

FIG. 16 illustrates an exemplary method of treating a nerve according tosome embodiments;

FIG. 17 illustrates another exemplary method of locating and treating anerve according to some embodiments;

FIG. 18A illustrates an exemplary needle assembly according to someembodiments;

FIG. 18B illustrates a close up view of a needle of the exemplary needleassembly of FIG. 18A according to some embodiments;

FIG. 18C illustrates an exemplary needle configuration according to someembodiments;

FIG. 19 illustrates an exemplary treatment system with a replaceableneedle assembly having an electrical port for coupling with a waveformgenerator of a percutaneous electrical stimulation device according tosome embodiments;

FIG. 20 illustrates the exemplary replaceable needle assembly of FIG. 19according to some embodiments;

FIG. 21 illustrates yet another exemplary treatment system with a handlehaving an electrical port for coupling with a waveform generator of apercutaneous electrical nerve stimulation device according to someembodiments;

FIG. 22 illustrates a view of a proximal end of the exemplary treatmentsystem of FIG. 21 according to some embodiments;

FIG. 23 illustrates yet another exemplary treatment system with a fullyintegrated percutaneous electrical stimulation device according to someembodiments;

FIG. 24 illustrates another exemplary needle assembly according to someembodiments;

FIG. 25 illustrates an exemplary treatment system with an integratedtranscutaneous electrical nerve stimulation probe according to someembodiments;

FIG. 26 illustrates an exemplary operation of the exemplary system ofFIG. 24 according to some embodiments.

DETAILED DESCRIPTION

The present invention provides improved medical devices, systems, andmethods. Embodiments of the invention may treat target tissues disposedat and below the skin, optionally to treat pain associated with asensory nerve. In some embodiments, systems, devices, and methods of thepresent disclosure may utilize an integrated nerve stimulation devicefor localization of a target nerve.

Embodiments of the invention may utilize a handheld refrigeration systemthat can use a commercially available cartridge of fluid refrigerant.Refrigerants well suited for use in handheld refrigeration systems mayinclude nitrous oxide and carbon dioxide. These can achieve temperaturesapproaching −90° C.

Sensory nerves and associated tissues may be temporarily impaired usingmoderately cold temperatures of 10° C. to −5° C. without permanentlydisabling the tissue structures. Using an approach similar to thatemployed for identifying structures associated with atrial fibrillationor for peripheral nerve blocks, a needle probe or other treatment devicecan be used to identify a target tissue structure in a diagnostic modewith these moderate temperatures, and the same probe (or a differentprobe) can also be used to provide a longer term or permanent treatment,optionally by treating the target tissue zone and/or inducing apoptosisat temperatures from about −5° C. to about −50° C. In some embodiments,apoptosis may be induced using treatment temperatures from about −1° C.to about −15° C., or from about −1° C. to about −19° C., optionally soas to provide a longer lasting treatment that limits or avoidsinflammation and mobilization of skeletal muscle satellite repair cells.In some embodiments, axonotmesis with Wallerian degeneration of asensory nerve is desired, which may be induced using treatmenttemperatures from about −20° C. to about −100° C. Hence, the duration ofthe treatment efficacy of such subdermal cryogenic treatments may beselected and controlled, with colder temperatures, longer treatmenttimes, and/or larger volumes or selected patterns of target tissuedetermining the longevity of the treatment. Additional description ofcryogenic cooling methods and devices may be found in commonly assignedU.S. Pat. No. 7,713,266 entitled “Subdermal Cryogenic Remodeling ofMuscle, Nerves, Connective Tissue, and/or Adipose Tissue (Fat)”; U.S.Pat. No. 7,850,683 entitled “Subdermal Cryogenic Remodeling of Muscles,Nerves, Connective Tissue, and/or Adipose Tissue (Fat)”; U.S. Pat. No.9,039,688 entitled “Method for Reducing Hyperdynamic Facial Wrinkles”;and U.S. Pat. No. 8,298,216 entitled “Pain Management Using CryogenicRemodeling,” the full disclosures of which are each incorporated byreference herein.

Referring now to FIGS. 1A and 1B, a system for cryogenic remodeling herecomprises a self-contained probe handpiece generally having a proximalend 12 and a distal end 14. A handpiece body or housing 16 has a sizeand ergonomic shape suitable for being grasped and supported in asurgeon's hand or other system operator. As can be seen most clearly inFIG. 1B, a cryogenic cooling fluid supply 18, a supply valve 32 andelectrical power source 20 are found within housing 16, along with acircuit 22S having a processor for controlling cooling applied byself-contained system 10 in response to actuation of an input 24.Alternatively, electrical power can be applied through a cord from aremote power source. Power source 20 also supplies power to heaterelement 44 in order to heat the proximal region of probe 26 which maythereby help to prevent unwanted skin damage, and a temperature sensor48 adjacent the proximal region of probe 26 helps monitor probetemperature. Additional details on the heater 44 and temperature sensor48 are described in greater detail below. When actuated, supply valve 32controls the flow of cryogenic cooling fluid from fluid supply 18. Someembodiments may, at least in part, be manually activated, such asthrough the use of a manual supply valve and/or the like, so thatprocessors, electrical power supplies, and the like may not be required.

Extending distally from distal end 14 of housing 16 may be atissue-penetrating cryogenic cooling probe 26. Probe 26 is thermallycoupled to a cooling fluid path extending from cooling fluid source 18,with the exemplary probe comprising a tubular body receiving at least aportion of the cooling fluid from the cooling fluid source therein. Theexemplary probe 26 may comprise a 30 G needle having a sharpened distalend that is axially sealed. Probe 26 may have an axial length betweendistal end 14 of housing 16 and the distal end of the needle of betweenabout 0.5 mm and 15 cm. Such needles may comprise a stainless steel tubewith an inner diameter of about 0.006 inches and an outer diameter ofabout 0.012 inches, while alternative probes may comprise structureshaving outer diameters (or other lateral cross-sectional dimensions)from about 0.006 inches to about 0.100 inches. Generally, needle probe26 may comprise a 16 GA or smaller size needle, often comprising a 20 GAneedle or smaller, typically comprising a 25, 26, 27, 28, 29, or 30 GAor smaller needle.

In some embodiments, probe 26 may comprise two or more needles arrangedin a linear array, such as those disclosed in previously incorporatedU.S. Pat. No. 7,850,683. Another exemplary embodiment of a probe havingmultiple needle probe configurations allow the cryogenic treatment to beapplied to a larger or more specific treatment area. Other needleconfigurations that facilitate controlling the depth of needlepenetration and insulated needle embodiments are disclosed in commonlyassigned U.S. Pat. No. 8,409,185 entitled “Replaceable and/or EasilyRemovable Needle Systems for Dermal and Transdermal CryogenicRemodeling,” the entire content of which is incorporated herein byreference. Multiple needle arrays may also be arrayed in alternativeconfigurations such as a triangular or square array.

Arrays may be designed to treat a particular region of tissue, or toprovide a uniform treatment within a particular region, or both. In someembodiments needle 26 may be releasably coupled with body 16 so that itmay be replaced after use with a sharper needle (as indicated by thedotted line) or with a needle having a different configuration. Inexemplary embodiments, the needle may be threaded into the body, pressfit into an aperture in the body or have a quick disconnect such as adetent mechanism for engaging the needle with the body. A quickdisconnect with a check valve may be advantageous since it may permitdecoupling of the needle from the body at any time without excessivecoolant discharge. This can be a useful safety feature in the event thatthe device fails in operation (e.g., valve failure), allowing anoperator to disengage the needle and device from a patient's tissuewithout exposing the patient to coolant as the system depressurizes.This feature may also be advantageous because it allows an operator toeasily exchange a dull needle with a sharp needle in the middle of atreatment. One of skill in the art will appreciate that other couplingmechanisms may be used.

Addressing some of the components within housing 16, the exemplarycooling fluid supply 18 may comprise a canister, sometimes referred toherein as a cartridge, containing a liquid under pressure, with theliquid preferably having a boiling temperature of less than 37° C. atone atmosphere of pressure. When the fluid is thermally coupled to thetissue-penetrating probe 26, and the probe is positioned within thepatient so that an outer surface of the probe is adjacent to a targettissue, the heat from the target tissue evaporates at least a portion ofthe liquid and the enthalpy of vaporization cools the target tissue. Asupply valve 32 may be disposed along the cooling fluid flow pathbetween canister 18 and probe 26, or along the cooling fluid path afterthe probe so as to limit coolant flow thereby regulating thetemperature, treatment time, rate of temperature change, or othercooling characteristics. The valve will often be powered electricallyvia power source 20, per the direction of processor 22, but may at leastin part be manually powered. The exemplary power source 20 comprises arechargeable or single-use battery. Additional details about valve 32are disclosed below and further disclosure on the power source 20 may befound in commonly assigned Int'l Pub. No. WO 2010/075438 entitled“Integrated Cryosurgical Probe Package with Fluid Reservoir and LimitedElectrical Power Source,” the entire contents of which are incorporatedherein by reference.

The exemplary cooling fluid supply 18 may comprise a single-usecanister. Advantageously, the canister and cooling fluid therein may bestored and/or used at (or even above) room temperature. The canister mayhave a frangible seal or may be refillable, with the exemplary canistercontaining liquid nitrous oxide, N2O. A variety of alternative coolingfluids might also be used, with exemplary cooling fluids includingfluorocarbon refrigerants and/or carbon dioxide. The quantity of coolingfluid contained by canister 18 will typically be sufficient to treat atleast a significant region of a patient, but will often be less thansufficient to treat two or more patients. An exemplary liquid N2Ocanister might contain, for example, a quantity in a range from about 1gram to about 40 grams of liquid, more preferably from about 1 gram toabout 35 grams of liquid, and even more preferably from about 7 grams toabout 30 grams of liquid.

Processor 22 will typically comprise a programmable electronicmicroprocessor embodying machine readable computer code or programminginstructions for implementing one or more of the treatment methodsdescribed herein. The microprocessor will typically include or becoupled to a memory (such as a non-volatile memory, a flash memory, aread-only memory (“ROM”), a random access memory (“RAM”), or the like)storing the computer code and data to be used thereby, and/or arecording media (including a magnetic recording media such as a harddisk, a floppy disk, or the like; or an optical recording media such asa CD or DVD) may be provided. Suitable interface devices (such asdigital-to-analog or analog-to-digital converters, or the like) andinput/output devices (such as USB or serial I/O ports, wirelesscommunication cards, graphical display cards, and the like) may also beprovided. A wide variety of commercially available or specializedprocessor structures may be used in different embodiments, and suitableprocessors may make use of a wide variety of combinations of hardwareand/or hardware/software combinations. For example, processor 22 may beintegrated on a single processor board and may run a single program ormay make use of a plurality of boards running a number of differentprogram modules in a wide variety of alternative distributed dataprocessing or code architectures.

Referring now to FIG. 2A, schematic 11 shows a simplified diagram ofcryogenic cooling fluid flow and control. The flow of cryogenic coolingfluid from fluid supply 18 may be controlled by a supply valve 32.Supply valve 32 may comprise an electrically actuated solenoid valve, amotor actuated valve or the like operating in response to controlsignals from controller 22, and/or may comprise a manual valve.Exemplary supply valves may comprise structures suitable for on/offvalve operation, and may provide venting of the fluid source and/or thecooling fluid path downstream of the valve when cooling flow is haltedso as to limit residual cryogenic fluid vaporization and cooling.Additionally, the valve may be actuated by the controller in order tomodulate coolant flow to provide high rates of cooling in some instanceswhere it is desirable to promote necrosis of tissue such as in malignantlesions and the like or slow cooling which promotes ice formationbetween cells rather than within cells when necrosis is not desired.More complex flow modulating valve structures might also be used inother embodiments. For example, other applicable valve embodiments aredisclosed in previously incorporated U.S. Pat. No. 8,409,185.

Still referring to FIG. 2A, an optional heater (not illustrated) may beused to heat cooling fluid supply 18 so that heated cooling fluid flowsthrough valve 32 and through a lumen 34 of a cooling fluid supply tube36. In some embodiments a safety mechanism can be included so that thecooling supply is not overheated. Examples of such embodiments aredisclosed in commonly assigned International Publication No. WO2010075438, the entirety of which is incorporated by reference herein.

Supply tube 36 is, at least in part, disposed within a lumen 38 ofneedle 26, with the supply tube extending distally from a proximal end40 of the needle toward a distal end 42. The exemplary supply tube 36comprises a fused silica tubular structure (not illustrated) having apolymer coating and extending in cantilever into the needle lumen 38.Supply tube 36 may have an inner lumen with an effective inner diameterof less than about 200 μm, the inner diameter often being less thanabout 100 μm, and typically being less than about 40 μm. Exemplaryembodiments of supply tube 36 have inner lumens of between about 15 and50 μm, such as about 30 μm. An outer diameter or size of supply tube 36will typically be less than about 1000 μm, often being less than about800 μm, with exemplary embodiments being between about 60 and 150 μm,such as about 90 μm or 105 μm. The tolerance of the inner lumen diameterof supply tubing 36 will preferably be relatively tight, typically beingabout +/−10 μm or tighter, often being +/−5 μm or tighter, and ideallybeing +/−3 μm or tighter (e.g., +/−1 μm), as the small diameter supplytube may provide the majority of (or even substantially all of) themetering of the cooling fluid flow into needle 26. Additional details onvarious aspects of needle 26 along with alternative embodiments andprinciples of operation are disclosed in greater detail in U.S. Pat. No.9,254,162 entitled “Dermal and Transdermal Cryogenic Microprobe Systemsand Methods,” the entire contents of which are incorporated herein byreference. Previously incorporated U.S. Pat. No. 8,409,185 alsodiscloses additional details on the needle 26 along with variousalternative embodiments and principles of operation.

The cooling fluid injected into lumen 38 of needle 26 will typicallycomprise liquid, though some gas may also be injected. At least some ofthe liquid vaporizes within needle 26, and the enthalpy of vaporizationcools the needle and also the surrounding tissue engaged by the needle.An optional heater 44 (illustrated in FIG. 1B) may be used to heat theproximal region of the needle in order to prevent unwanted skin damagein this area, as discussed in greater detail below. Controlling apressure of the gas/liquid mixture within needle 26 substantiallycontrols the temperature within lumen 38, and hence the treatmenttemperature range of the tissue. A relatively simple mechanical pressurerelief valve 46 may be used to control the pressure within the lumen ofthe needle, with the exemplary valve comprising a valve body such as aball bearing, urged against a valve seat by a biasing spring. Anexemplary relief valve is disclosed in U.S. Provisional PatentApplication No. 61/116,050 previously incorporated herein by reference.Thus, the relief valve may allow better temperature control in theneedle, minimizing transient temperatures. Further details on exhaustvolume are disclosed in previously incorporated U.S. Pat. No. 8,409,185.

The heater 44 may be thermally coupled to a thermally responsive element50, which is supplied with power by the controller 22 and thermallycoupled to a proximal portion of the needle 26. The thermally responsiveelement 50 can be a block constructed from a material of high thermalconductivity and low heat capacity, such as aluminum. A firsttemperature sensor 52 (e.g., thermistor, thermocouple) can also bethermally coupled the thermally responsive element 50 andcommunicatively coupled to the controller 22. A second temperaturesensor 53 can also be positioned near the heater 44, for example, suchthat the first temperature sensor 52 and second temperature sensor 53are placed in different positions within the thermally responsiveelement 50. In some embodiments, the second temperature sensor 53 isplaced closer to a tissue contacting surface than the first temperaturesensor 52 is placed in order to provide comparative data (e.g.,temperature differential) between the sensors 52, 53. The controller 22can be configured to receive temperature information of the thermallyresponsive element 50 via the temperature sensor 52 in order to providethe heater 44 with enough power to maintain the thermally responsiveelement 50 at a particular temperature.

The controller 22 can be further configured to monitor power draw fromthe heater 44 in order to characterize tissue type, perform devicediagnostics, and/or provide feedback for a tissue treatment algorithm.This can be advantageous over monitoring temperature alone, since powerdraw from the heater 44 can vary greatly while temperature of thethermally responsive element 50 remains relatively stable. For example,during treatment of target tissue, maintaining the thermally responsiveelement 50 at 40° C. during a cooling cycle may take 1.0 W initially(for a needle <10 mm in length) and is normally expected to climb to 1.5W after 20 seconds, due to the needle 26 drawing in surrounding heat. Anindication that the heater is drawing 2.0 W after 20 seconds to maintain40° C. can indicate that an aspect of the system 10 is malfunctioningand/or that the needle 26 is incorrectly positioned. Correlations withpower draw and correlated device and/or tissue conditions can bedetermined experimentally to determine acceptable treatment powerranges.

In some embodiments, it may be preferable to limit frozen tissue that isnot at the treatment temperature, i.e., to limit the size of a formedcooling zone within tissue. Such cooling zones may be associated with aparticular physical reaction, such as the formation of an ice-ball, orwith a particular temperature profile or temperature volume gradientrequired to therapeutically affect the tissue therein. To achieve this,metering coolant flow could maintain a large thermal gradient at itsoutside edges. This may be particularly advantageous in applications forcreating an array of connected cooling zones (i.e., fence) in atreatment zone, as time would be provided for the treatment zone tofully develop within the fenced in portion of the tissue, while theouter boundaries maintained a relatively large thermal gradient due tothe repeated application and removal of refrigeration power. This couldprovide a mechanism within the body of tissue to thermally regulate thetreatment zone and could provide increased ability to modulate thetreatment zone at a prescribed distance from the surface of the skin. Arelated treatment algorithm could be predefined, or it could be inresponse to feedback from the tissue.

Such feedback could be temperature measurements from the needle 26, orthe temperature of the surface of the skin could be measured. However,in many cases monitoring temperature at the needle 26 is impractical dueto size constraints. To overcome this, operating performance of thesensorless needle 26 can be interpolated by measuring characteristics ofthermally coupled elements, such as the thermally responsive element 50.

Additional methods of monitoring cooling and maintaining an unfrozenportion of the needle include the addition of a heating element and/ormonitoring element into the needle itself. This could consist of a smallthermistor or thermocouple, and a wire that could provide resistiveheat. Other power sources could also be applied such as infrared light,radiofrequency heat, and ultrasound. These systems could also be appliedtogether dependent upon the control of the treatment zone desired.

Alternative methods to inhibit excessively low transient temperatures atthe beginning of a refrigeration cycle might be employed instead of ortogether with the limiting of the exhaust volume. For example, thesupply valve 32 might be cycled on and off, typically by controller 22,with a timing sequence that would limit the cooling fluid flowing sothat only vaporized gas reached the needle lumen 38 (or a sufficientlylimited amount of liquid to avoid excessive dropping of the needle lumentemperature). This cycling might be ended once the exhaust volumepressure was sufficient so that the refrigeration temperature would bewithin desired limits during steady state flow. Analytical models thatmay be used to estimate cooling flows are described in greater detail inpreviously incorporated U.S. Pat. No. 9,254,162.

FIG. 2B shows a cross-section of the housing 16. This embodiment of thehousing 16 may be powered by an external source, hence the attachedcable, but could alternatively include a portable power source. Asshown, the housing includes a cartridge holder 50. The cartridge holder50 includes a cartridge receiver 52, which may be configured to hold apressured refrigerant cartridge 18. The cartridge receiver 52 includesan elongated cylindrical passage 70, which is dimensioned to hold acommercially available cooling fluid cartridge 18. A distal portion ofthe cartridge receiver 52 includes a filter device 56, which has anelongated conical shape. In some embodiments, the cartridge holder 50may be largely integrated into the housing 16 as shown, however, inalternative embodiments, the cartridge holder 50 is a wholly separateassembly, which may be pre-provided with a coolant fluid source 18.

The filter device 56 may fluidly couple the coolant fluid source(cartridge) 18 at a proximal end to the valve 32 at a distal end. Thefilter device 56 may include at least one particulate filter 58. In theshown embodiment, a particulate filter 58 at each proximal and distalend of the filter device 56 may be included. The particulate filter 58can be configured to prevent particles of a certain size from passingthrough. For example, the particulate filter 58 can be constructed as amicroscreen having a plurality of passages less than 2 microns in width,and thus particles greater than 2 microns would not be able to pass.

The filter device 56 also includes a molecular filter 60 that isconfigured to capture fluid impurities. In some embodiments, themolecular filter 60 is a plurality of filter media (e.g., pellets,powder, particles) configured to trap molecules of a certain size. Forexample, the filter media can comprise molecular sieves having poresranging from 1-20 Å. In another example, the pores have an average sizeof 5 Å. The molecular filter 60 can have two modalities. In a firstmode, the molecular filter 60 will filter fluid impurities received fromthe cartridge 18. However, in another mode, the molecular filter 60 cancapture impurities within the valve 32 and fluid supply tube 36 when thesystem 10 is not in use, i.e., when the cartridge 18 is not fluidlyconnected to the valve 32.

Alternatively, the filter device 56 can be constructed primarily fromePTFE (such as a GORE material), sintered polyethylene (such as made byPOREX), or metal mesh. The pore size and filter thickness can beoptimized to minimize pressure drop while capturing the majority ofcontaminants. These various materials can be treated to make ithydrophobic (e.g., by a plasma treatment) and/or oleophobic so as torepel water or hydrocarbon contaminants.

It has been found that in some instances fluid impurities may leach outfrom various aspects of the system 10. These impurities can includetrapped moisture in the form of water molecules and chemical gasses. Thepresence of these impurities is believed to hamper cooling performanceof the system 10. The filter device 56 can act as a desiccant thatattracts and traps moisture within the system 10, as well as chemicalsout gassed from various aspects of the system 10. Alternately thevarious aspects of the system 10 can be coated or plated withimpermeable materials such as a metal.

As shown in FIG. 2B and in more detail in FIG. 2C and FIG. 2D, thecartridge 18 can be held by the cartridge receiver 52 such that thecartridge 18 remains intact and unpunctured. In this inactive mode, thecartridge may not be fluidly connected to the valve 32. A removablecartridge cover 62 can be attached to the cartridge receiver 52 suchthat the inactive mode is maintained while the cartridge is held by thesystem 10.

In use, the cartridge cover 62 can be removed and supplied with acartridge containing a cooling fluid. The cartridge cover 62 can then bereattached to the cartridge receiver 52 by turning the cartridge cover62 until female threads 64 of the cartridge cover 62 engage with malethreads of the cartridge receiver 52. The cartridge cover 62 can beturned until resilient force is felt from an elastic seal 66, as shownin FIG. 2C. To place the system 10 into use, the cartridge cover 62 canbe further turned until the distal tip of the cartridge 18 is puncturedby a puncture pin connector 68, as shown in FIG. 2D. Once the cartridge18 is punctured, cooling fluid may escape the cartridge by flowingthrough the filter device 56, where the impurities within the coolingfluid may be captured. The purified cooling fluid then passes to thevalve 32, and onto the coolant supply tube 36 to cool the probe 26. Insome embodiments the filter device, or portions thereof, may bereplaceable.

In some embodiments, the puncture pin connector 68 can have a two-wayvalve (e.g., ball/seat and spring) that is closed unless connected tothe cartridge. Alternately, pressure can be used to open the valve. Thevalve closes when the cartridge is removed. In some embodiments, theremay be a relief valve piloted by a spring which is balanced byhigh-pressure nitrous when the cartridge is installed and the system ispressurized, but allows the high-pressure cryogen to vent when thecryogen is removed. In addition, the design can include a vent port thatvents cold cryogen away from the cartridge port. Cold venting cryogenlocally can cause condensation in the form of liquid water to form fromthe surrounding environment. Liquid water or water vapor entering thesystem can hamper the cryogenic performance. Further, fluid carryingportions of the cartridge receiver 52 can be treated (e.g., plasmatreatment) to become hydrophobic and/or oleophobic so as to repel wateror hydrocarbon contaminants.

Turning now to FIG. 3A and FIG. 3B, an exemplary embodiment of probe 300having multiple needles 302 is described. In FIG. 3A, probe housing 316includes threads 306 that allow the probe to be threadably engaged withthe housing 16 of a cryogenic device. O-rings 308 fluidly seal the probehousing 316 with the device housing 16 and prevent coolant from leakingaround the interface between the two components. Probe 300 includes anarray of three distally extending needle shafts 302, each having asharpened, tissue penetrating tip 304. In certain embodiments, usingthree linearly arranged needles allows a greater area of tissue to betreated as compared with a single needle. In use, coolant flows throughlumens 310 into the needle shafts 302 thereby cooling the needle shafts302. Ideally, only the distal portion of the needle shaft 302 would becooled so that only the target tissue receives the cryogenic treatment.However, as the cooling fluid flows through the probe 300, probetemperature decreases proximally along the length of the needle shafts302 towards the probe hub 318. The proximal portion of needle shaft 302and the probe hub 318 contact skin and may become very cold (e.g. −20°C. to −25° C.) and this can damage the skin in the form of blistering orloss of skin pigmentation. Therefore it would be desirable to ensurethat the proximal portion of needle shaft 302 and hub 318 remains warmerthan the distal portion of needle shaft 302. A proposed solution to thischallenge is to include a heater element 314 that can heat the proximalportion of needle shaft 302 and an optional temperature sensor 312 tomonitor temperature in this region. To further this, a proximal portionof the needle shaft 302 can be coated with a highly thermally conductivematerial, e.g., gold, that is conductively coupled to both the needleshaft 302 and heater element 314. Details of this construction aredisclosed below.

In the exemplary embodiment of FIG. 3A, resistive heater element 314 isdisposed near the needle hub 318 and near a proximal region of needleshaft 302. The resistance of the heater element is preferably 1Ω to 1KΩ,and more preferably from 5Ω to 50Ω. Additionally, a temperature sensor312 such as a thermistor or thermocouple is also disposed in the samevicinity. Thus, during a treatment as the needles cool down, the heater314 may be turned on in order to heat the hub 318 and proximal region ofneedle shaft 302, thereby preventing this portion of the device fromcooling down as much as the remainder of the needle shaft 302. Thetemperature sensor 312 may provide feedback to controller 22 and afeedback loop can be used to control the heater 314. The cooling powerof the nitrous oxide may eventually overcome the effects of the heater,therefore the microprocessor may also be programmed with a warning lightand/or an automatic shutoff time to stop the cooling treatment beforeskin damage occurs. An added benefit of using such a heater element isthe fact that the heat helps to moderate the flow of cooling fluid intothe needle shaft 302 helping to provide more uniform coolant mass flowto the needles shaft 302 with more uniform cooling resulting.

The embodiment of FIG. 3A illustrates a heater fixed to the probe hub.In other embodiments, the heater may float, thereby ensuring proper skincontact and proper heat transfer to the skin. Examples of floatingheaters are disclosed in commonly assigned Int'l Pub. No. WO 2010/075448entitled “Skin Protection for Subdermal Cryogenic Remodeling forCosmetic and Other Treatments,” the entirety of which is incorporated byreference herein.

In this exemplary embodiment, three needles are illustrated. One ofskill in the art will appreciate that a single needle may be used, aswell as two, four, five, six, or more needles may be used. When aplurality of needles are used, they may be arranged in any number ofpatterns. For example, a single linear array may be used, or a twodimensional or three dimensional array may be used. Examples of twodimensional arrays include any number of rows and columns of needles(e.g., a rectangular array, a square array, elliptical, circular,triangular, etc.), and examples of three dimensional arrays includethose where the needle tips are at different distances from the probehub, such as in an inverted pyramid shape.

FIG. 3B illustrates a cross-section of the needle shaft 302 of needleprobe 300. The needle shaft can be conductively coupled (e.g., welded,conductively bonded, press fit) to a conductive heater 314 to enableheat transfer therebetween. The needle shaft 302 is generally a small(e.g., 20-30 gauge) closed tip hollow needle, which can be between about0.2 mm and 15 cm, preferably having a length from about 0.3 cm to about3 cm. The conductive heater element 314 can be housed within aconductive block 315 of high thermally conductive material, such asaluminum and include an electrically insulated coating, such as Type IIIanodized coating to electrically insulate it without diminishing itsheat transfer properties. The conductive block 315 can be heated by aresister or other heating element (e.g., cartridge heater, nichromewire, etc.) bonded thereto with a heat conductive adhesive, such asepoxy. A thermistor can be coupled to the conductive block 315 with heatconductive epoxy allows temperature monitoring. Other temperaturesensors may also be used, such as a thermocouple.

A cladding 320 of conductive material is directly conductively coupledto the proximal portion of the shaft of the needle 302, which can bestainless steel. In some embodiments, the cladding 320 is a layer ofgold, or alloys thereof, coated on the exterior of the proximal portionof the needle shaft 302. In some embodiments, the exposed length ofcladding 320 on the proximal portion of the needle is 2-100 mm. In someembodiments, the cladding 320 can be of a thickness such that the cladportion has a diameter ranging from 0.017-0.020 in., and in someembodiments 0.0182 in. Accordingly, the cladding 320 can be conductivelycoupled to the material of the needle 302, which can be less conductive,than the cladding 320. The cladding 320 may modify the lateral forcerequired to deflect or bend the needle 26. Cladding 320 may be used toprovide a stiffer needle shaft along the proximal end in order to moreeasily transfer force to the leading tip during placement and allow thedistal portion of the needle to deflect more easily when it isdissecting a tissue interface within the body. The stiffness of needle26 can vary from one end to the other end by other means such asmaterial selection, metal tempering, variation of the inner diameter ofthe needle 26, or segments of needle shaft joined together end-to-end toform one contiguous needle 26. In some embodiments, increasing thestiffness of the distal portion of the needle 26 can be used to flex theproximal portion of the needle to access difficult treatment sites as inthe case of upper limb spasticity where bending of the needle outsidethe body may be used to access a target peripheral nerve along thedesired tissue plane.

In some embodiments, the cladding 320 can include sub-coatings (e.g.,nickel) that promote adhesion of an outer coating that would otherwisenot bond well to the needle shaft 302. Other highly conductive materialscan be used as well, such as copper, silver, aluminum, and alloysthereof. In some embodiments, a protective polymer or metal coating cancover the cladding to promote biocompatibility of an otherwisenon-biocompatible but highly conductive cladding material. Such abiocompatible coating however, would be applied to not disruptconductivity between the conductive block 315. In some embodiments, aninsulating layer, such as a ceramic material, is coated over thecladding 320, which remains conductively coupled to the needle shaft302.

In use, the cladding 320 can transfer heat to the proximal portion ofthe needle 302 to prevent directly surrounding tissue from dropping tocryogenic temperatures. Protection can be derived from heating thenon-targeting tissue during a cooling procedure, and in some embodimentsbefore the procedure as well. The mechanism of protection may beproviding heat to pressurized cryogenic cooling fluid passing within theproximal portion of the needle to affect complete vaporization of thefluid. Thus, the non-target tissue in contact with the proximal portionof the needle shaft 302 does not need to supply heat, as opposed totarget tissue in contact with the distal region of the needle shaft 302.To help further this effect, in some embodiments the cladding 320 iscoating within the interior of the distal portion of the needle, with orwithout an exterior cladding. To additionally help further this effect,in some embodiments, the distal portion of the needle can be thermallyisolated from the proximal portion by a junction, such as a ceramicjunction. While in some further embodiments, the entirety of theproximal portion is constructed from a more conductive material than thedistal portion.

In use, it has been determined experimentally that the cladding 320 canhelp limit formation of a cooling zone to the distal portion of theneedle shaft 302, which tends to demarcate at a distal end of thecladding 320. Accordingly, cooling zones are formed only about thedistal portions of the needles. Thus, non-target tissue in directcontact with proximal needle shafts remain protected from effects ofcryogenic temperatures. Such effects can include discoloration andblistering of the skin. Such cooling zones may be associated with aparticular physical reaction, such as the formation of an ice-ball, orwith a particular temperature required to therapeutically affect thetissue therein.

Standard stainless steel needles and gold clad steel needles were testedin porcine muscle and fat. Temperatures were recorded measured 2 mm fromthe proximal end of the needle shafts, about where the cladding distallyterminates, and at the distal tip of the needles. Temperatures for cladneedles were dramatically warmer at the 2 mm point versus the uncladneedles, and did not drop below 4° C. The 2 mm points of the standardstainless steel needles almost equalize in temperature with the distaltip at temperatures below 0° C.

FIGS. 3C and 3D illustrates a detachable probe tip 322 having a hubconnector 324 and an elongated probe 326. The probe tip 322 shares muchof its construction with probe 300. However, the elongated probe 326features a blunt tip 328 that is adapted for blunt dissection of tissue.The blunt tip 328 can feature a full radius tip, less than a full radiustip, or conical tip. In some embodiments, a dulled or truncated needleis used. The elongated probe 326 can be 20 gauge or smaller in diameter,and in some embodiments range in size from 25-30 gauge. As with theembodiments described above, an internal supply tube 330 extends incantilever. However, the exit of the supply tube 330 can be disposed atpositions within the elongated probe 326 other than proximate the blunttip 328. Further, the supply tube 330 can be adapted to create anelongated zone of cooling, e.g., by having multiple exit points forcryofluid to exit from.

The elongated probe 326 and supply tube 330 may be configured toresiliently bend in use, throughout their length at angles approaching120°, with a 5-10 mm bend radius. This may be very challengingconsidering the small sizes of the elongated probe 326 and supply tube330, and also considering that the supply tube 330 is often constructedfrom fused silica. Accordingly, the elongated probe 326 can beconstructed from a resilient material, such as stainless steel, and of aparticular diameter and wall thickness [0.004 to 1.0 mm], such that theelongated probe in combination with the supply tube 330 is not overlyresilient so as to overtly resist manipulation, but sufficiently strongso as to prevent kinking that can result in coolant escaping. Forexample, the elongated probe can be 15 gauge or smaller in diameter,even ranging from 20-30 gauge in diameter. The elongated probe can havea very disparate length to diameter ratio, for example, the elongatedprobe can be greater than 30 mm in length, and in some cases range from30-100 mm in length. To further the aforementioned goals, the supplytube 330 can include a polymer coating 332, such as a polyimide coatingthat terminates approximately halfway down its length, to resist kinkingand aid in resiliency. The polymer coating 332 can be a secondarycoating over a primary polyimide coating that extends fully along thesupply tube. However, it should be understood that the coating is notlimited to polyimide, and other suitable materials can be used. In someembodiments, the flexibility of the elongated probe 326 will vary fromthe proximal end to the distal end. For example, by creating certainportions that have more or less flexibility than others. This may bedone, for example, by modifying wall thickness, adding material (such asthe cladding discussed above), and/or heat treating certain portions ofthe elongated probe 326 and/or supply tube 330. For example, decreasingthe flexibility of elongated probe 326 along the proximal end canimprove the transfer of force from the hand piece to the elongated probeend for better feel and easier tip placement for treatment. Theelongated probe and supply line 330 may be configured to resilientlybend in use to different degrees along the length at angles approaching120°, with a varying bend radius as small as 5 mm. In some embodiments,the elongated probe 326 will have external markings along the needleshaft indicating the length of needle inserted into the tissue.

FIG. 3E illustrates an exemplary detachable probe tip 322 insertedthrough skin surface SS. As illustrated, the probe tip 322 is insertedalong an insertion axis IA through the skin surface SS. Thereafter, theneedle may be bent away from the insertion axis IA and advanced toward atarget tissue TT in order to position blunt tip 328 adjacent to thetarget tissue TT. In some embodiments, the target tissue may be theinfrapatellar branch of the saphenous nerve. In other embodiments thetarget tissue may be one or more branches of the anterior femoralcutaneous nerve or the lateral femoral cutaneous nerve.

In some embodiments, the probe tip 322 does not include a heatingelement, such as the heater described with reference to probe 300, sincethe effective treating portion of the elongated probe 326 (i.e., thearea of the elongated probe where a cooling zone emanates from) is welllaterally displaced from the hub connector 324 and elongated probeproximal junction. Embodiments of the supply tube are further describedbelow and within commonly assigned U.S. Pub. No. 2012/0089211, which isincorporated by reference.

FIGS. 4A-4C illustrate an exemplary method of creating a hole throughthe skin that allows multiple insertions and positioning of a cryoprobetherethrough. This may be helpful when the needle must be advanceddistally past dense scar tissue. In FIG. 4A a cannula or sheath 1902 isdisposed over a needle 1904 having a tissue penetrating distal end 1908.The cannula may have a tapered distal portion 1906 to help spread anddilate the skin during insertion. The needle/sheath assembly is thenadvanced into and pierces the skin 1910 into the desired target tissue1912. The inner pathway of the cannula or sheath 1902 may be curved toassist in directing the flexible needle 1904, or other probe, into adesired tissue layer coincident with the desired needle path in thetissue. Once the needle/sheath assembly has been advanced to a desiredlocation, the needle 1904 may be proximally retracted and removed fromthe sheath 1902. The sheath (or introducer) now may be used as an easyway of introducing a cryoprobe through the skin without piercing it, anddirecting the cryoprobe to the desired target treatment area. FIG. 4Bshows the sheath 1902 in position with the needle 1904 removed. FIG. 4Cshows insertion of a cryoprobe 1914 into the sheath such that a blunttip 1916 of the cryoprobe 1914 is adjacent the target treatment tissue.The cryoprobe may then be cooled and the treatment tissue cooled toachieve any of the cosmetic or therapeutic effects discussed above. Inthis embodiment, the cryoprobe preferably has a blunt tip 1916 in orderto minimize tissue trauma. In other embodiments, the tip may be sharpand be adapted to penetrate tissue, or it may be round and spherical.The cryoprobe 1914 may then be at least partially retracted from thesheath 1902 and/or rotated and then re-advanced to the same or differentdepth and repositioned in sheath 1902 so that the tip engages adifferent portion of the target treatment tissue without requiring anadditional piercing of the skin. The probe angle relative to the tissuemay also be adjusted, and the cryoprobe may be advanced and retractedmultiple times through the sheath so that the entire target tissue iscryogenically treated.

While the embodiment of FIGS. 4A-4C illustrates a cryoprobe having onlya single probe, the cryoprobe may have an array of probes. Any of thecryoprobes described above may be used with an appropriately sizedsheath. In some embodiments, the cryoprobe comprises a linear or twodimensional array of probes. Lidocaine or other local anesthetics may beused during insertion of the sheath or cryoprobe in order to minimizepatient discomfort. The angle of insertion for the sheath may beanywhere from 0 to 180 degrees relative to the skin surface, and inspecific embodiments is 15 to 45 degrees. The sheath may be inserted atany depth, but in specific embodiments of treating lines/wrinkles of theface, the sheath may be inserted to a depth of 1 mm to 10 mm, and morepreferably to a depth of 2 mm to 5 mm.

In an alternative embodiment seen in FIG. 4D, the sheath 1902 mayinclude an annular flange 1902 b on an outside surface of the sheath inorder to serve as a stop so that the sheath is only inserted a presetamount into the tissue. The position of the flange 1902 b may beadjustable or fixed. The proximal end of the sheath in this embodiment,or any of the other sheath embodiments may also include a one-way valvesuch as a hemostasis valve to prevent backflow of blood or other fluidsthat may exit the sheath. The sheath may also insulate a portion of thecryoprobe and prevent or minimize cooling of unwanted regions of tissue.

Any of the cryoprobes described above may be used with the sheathembodiment described above (e.g., in FIGS. 3B, 4A-4C). Other cryoprobesmay also be used with this sheath embodiment, or they may be used alone,in multi-probe arrays, or combined with other treatments. For example, aportion of the cryoprobe 2006 may be insulated as seen in FIG. 5.Cryoprobe 2006 includes a blunt tip 2004 with an insulated section 2008of the probe. Thus, when the cryoprobe is disposed in the treatmenttissue under the skin 2002 and cooled, the cryoprobe preferentiallycreates a cooling zone along one side while the other side remainsuncooled, or only experiences limited cooling. For example, in FIG. 5,the cooling zone 2010 is limited to a region below the cryoprobe 2006,while the region above the cryoprobe and below the skin 2002 remainunaffected by the cooling.

Different zones of cryotherapy may also be created by differentgeometries of the coolant fluid supply tube that is disposed in thecryoprobe. FIGS. 6-9 illustrate exemplary embodiments of differentcoolant fluid supply tubes. In FIG. 6 the coolant fluid supply tube 2106is offset from the central axis of a cryoprobe 2102 having a blunt tip2104. Additionally, the coolant fluid supply tube 2106 includes severalexit ports for the coolant including circular ports 2110, 2112 near thedistal end of the coolant fluid supply tube and an elliptical port 2108proximal of the other ports. These ports may be arranged in varyingsizes, and varying geometries in order to control the flow of cryofluidwhich in turn controls probe cooling of the target tissue. FIG. 7illustrates an alternative embodiment of a coolant fluid supply tube2202 having a plurality of circular ports 2204 for controlling cryofluidflow. FIG. 8 illustrates yet another embodiment of a coolant fluidsupply tube 2302 having a plurality of elliptical holes 2304, and FIG. 9shows still another embodiment of a coolant fluid supply tube 2402having a plurality of ports ranging from smaller diameter circular holes2404 near the distal end of the supply tube 2402 to larger diametercircular holes 2406 that are more proximally located on the supply tube2402.

As discussed above, it may be preferable to have a blunt tip on thedistal end of the cryoprobe in order to minimize tissue trauma. Theblunt tip may be formed by rounding off the distal end of the probe, ora bladder or balloon 2506 may be placed on the distal portion of theprobe 2504 as seen in FIG. 10. A filling tube or inflation lumen 2502may be integral with or separate from the cryoprobe 2504, and may beused to deliver fluid to the balloon to fill the balloon 2506 up to formthe atraumatic tip.

In some instances, it may be desirable to provide expandable cryoprobesthat can treat different target tissues or accommodate differentanatomies. For example, in FIGS. 11 and 12, a pair of cryoprobes 2606with blunt tips 2604 may be delivered in parallel with one another andin a low profile through a sheath 2602 to the treatment area. Oncedelivered, the probes may be actuated to separate the tips 2604 from oneanother, thereby increasing the cooling zone. After the cryotherapy hasbeen administered, the probes may be collapsed back into their lowprofile configuration, and retracted from the sheath.

In some embodiments, the probe may have a sharp tissue piercing distaltip, and in other embodiments, the probe may have a blunt tip forminimizing tissue trauma. To navigate through tissue, it may bedesirable to have a certain column strength for the probe in order toavoid bending, buckling or splaying, especially when the probe comprisestwo or more probes in an array. One exemplary embodiment may utilize avariable stiff portion of a sleeve along the probe body to provideadditional column strength for pushing the probe through tissue.

An exemplary algorithm 400 for controlling the heater element 314, andthus for transferring heat to the cladding 320, is illustrated in FIG.13. In FIG. 13, the start of the interrupt service routine (ISR) 402begins with reading the current needle hub temperature 404 using atemperature sensor such as a thermistor or thermocouple disposed nearthe needle hub. The time of the measurement is also recorded. This datais fed back to controller 22 where the slope of a line connecting twopoints is calculated. The first point in the line is defined by thecurrent needle hub temperature and time of its measurement and thesecond point consists of a previous needle hub temperature measurementand its time of measurement. Once the slope of the needle hubtemperature curve has been calculated 406, it is also stored 408 alongwith the time and temperature data. The needle hub temperature slope isthen compared with a slope threshold value 410. If the needle hubtemperature slope is less than the threshold value then a treating flagis activated 412 and the treatment start time is noted and stored 414.If the needle hub slope is greater than or equal to the slope thresholdvalue 410, an optional secondary check 416 may be used to verify thatcooling has not been initiated. In step 416, absolute needle hubtemperature is compared to a temperature threshold. If the hubtemperature is less than the temperature threshold, then the treatingflag is activated 412 and the treatment start time is recorded 414 aspreviously described. As an alternative, the shape of the slope could becompared to a norm, and an error flag could be activated for an out ofnorm condition. Such a condition could indicate the system was notheating or cooling sufficiently. The error flag could trigger anautomatic stop to the treatment with an error indicator light.Identifying the potential error condition and possibly stopping thetreatment may prevent damage to the proximal tissue in the form of toomuch heat, or too much cooling to the tissue. The algorithm preferablyuses the slope comparison as the trigger to activate the treatment flagbecause it is more sensitive to cooling conditions when the cryogenicdevice is being used rather than simply measuring absolute temperature.For example, a needle probe exposed to a cold environment wouldgradually cool the needle down and this could trigger the heater to turnon even though no cryogenic cooling treatment was being conducted. Theslope more accurately captures rapid decreases in needle temperature asare typically seen during cryogenic treatments.

When the treatment flag is activated 418 the needle heater is enabled420 and heater power may be adjusted based on the elapsed treatment timeand current needle hub temperature 422. Thus, if more heat is required,power is increased and if less heat is required, power is decreased.Whether the treatment flag is activated or not, as an additional safetymechanism, treatment duration may be used to control the heater element424. As mentioned above, eventually, cryogenic cooling of the needlewill overcome the effects of the heater element. In that case, it wouldbe desirable to discontinue the cooling treatment so that the proximalregion of the probe does not become too cold and cause skin damage.Therefore, treatment duration is compared to a duration threshold valuein step 424. If treatment duration exceeds the duration threshold thenthe treatment flag is cleared or deactivated 426 and the needle heateris deactivated 428. If the duration has not exceeded the durationthreshold 424 then the interrupt service routine ends 430. The algorithmthen begins again from the start step 402. This process continues aslong as the cryogenic device is turned on.

Preferred ranges for the slope threshold value may range from about −5°C. per second to about −90° C. per second and more preferably range fromabout −30° C. per second to about −57° C. per second. Preferred rangesfor the temperature threshold value may range from about 15° C. to about0° C., and more preferably may range from about 0° C. to about 10° C.Treatment duration threshold may range from about 15 seconds to about 75seconds.

It should be appreciated that the specific steps illustrated in FIG. 13provide a particular method of heating a cryogenic probe, according toan embodiment of the present invention. Other sequences of steps mayalso be performed according to alternative embodiments. For example,alternative embodiments of the present invention may perform the stepsoutlined above in a different order. Moreover, the individual stepsillustrated in FIG. 13 may include multiple sub-steps that may beperformed in various sequences as appropriate to the individual step.Furthermore, additional steps may be added or removed depending on theparticular applications.

The heating algorithm may be combined with a method for treating apatient. Referring now to FIG. 14, a method 100 facilitates treating apatient using a cryogenic cooling system having a reusable or disposablehandpiece either of which that can be self-contained or externallypowered with replaceable needles such as those of FIG. 1B and a limitedcapacity battery or metered electrical supply. Method 100 generallybegins with a determination 110 of the desired tissue therapy andresults, such as the inhibition of pain from a particular site.Appropriate target tissues for treatment are identified 112 (a tissuethat transmits the pain signal), allowing a target treatment depth,target treatment temperature profile, or the like to be determined. Step112 may include performing a tissue characterization and/or devicediagnostic algorithm, based on power draw of system 10, for example.

The application of the treatment algorithm 114 may include the controlof multiple parameters such as temperature, time, cycling, pulsing, andramp rates for cooling or thawing of treatment areas. In parallel withthe treatment algorithm 114, one or more power monitoring algorithms 115can be implemented. An appropriate needle assembly can then be mounted116 to the handpiece, with the needle assembly optionally having aneedle length, skin surface cooling chamber, needle array, and/or othercomponents suitable for treatment of the target tissues. Simpler systemsmay include only a single needle type, and/or a first needle assemblymounted to the handpiece.

Pressure, heating, cooling, or combinations thereof may be applied 118to the skin surface adjacent the needle insertion site before, during,and/or after insertion 120 and cryogenic cooling 122 of the needle andassociated target tissue. Non-target tissue directly above the targettissue can be protected by directly conducting energy in the form ofheat to the cladding on a proximal portion of the needle shaft duringcooling. Upon completion of the cryogenic cooling cycle the needles willneed additional “thaw” time 123 to thaw from the internally createdcooling zone to allow for safe removal of the probe without physicaldisruption of the target tissues, which may include, but not be limitedto nerves, muscles, blood vessels, or connective tissues. This thaw timecan either be timed with the refrigerant valve shut-off for as short atime as possible, preferably under 15 seconds, more preferably under 5seconds, manually or programmed into the controller to automaticallyshut-off the valve and then pause for a chosen time interval until thereis an audible or visual notification of treatment completion.

Heating of the needle may be used to prevent unwanted skin damage usingthe apparatus and methods previously described. The needle can then beretracted 124 from the target tissue. If the treatment is not complete126 and the needle is not yet dull 128, pressure and/or cooling can beapplied to the next needle insertion location site 118, and theadditional target tissue treated. However, as small gauge needles maydull after being inserted only a few times into the skin, any needlesthat are dulled (or otherwise determined to be sufficiently used towarrant replacement, regardless of whether it is after a singleinsertion, 5 insertions, or the like) during the treatment may bereplaced with a new needle 116 before the next application ofpressure/cooling 118, needle insertion 120, and/or the like. Once thetarget tissues have been completely treated, or once the cooling supplycanister included in the self-contained handpiece is depleted, the usedcanister and/or needles can be disposed of 130. The handpiece mayoptionally be discarded.

FIGS. 15A-15B illustrate a distal end of an exemplary cryoprobe 800 fortreating a nerve according to some embodiments. The probe 800 may have aneedle 805 extending distally that is configured to generate a cryozone810. In some embodiments, as illustrated in the close up of needle 805in FIG. 15B, the needle 805 may include one or more marks along thelength of the needle. The one or more marks may comprise a mark 815 formarking a distal end of the cryozone 810 that is generated by the probe800, a mark 820 for marking a proximal end of the cryozone 810 that isgenerated by the probe 800, and/or a mark 825 for marking a center of athe cryozone 810 that is generated by the probe 800.

The marks 815, 820, 825 may be utilized for visually aligning the needle805 of a probe 800 with a target nerve. For example, FIG. 16 illustratesan exemplary method 900 of treating a nerve according to someembodiments. At step 902, a needle of the cryotherapy probe ispositioned across the target nerve. The one or more markings indicativeof a treatment area (e.g., marks 815, 820, 825) of the needle may bealigned with the nerve 904. After alignment, the cryotherapy probe maybe activated to deliver the cooling therapy 906.

In some embodiments, the needle may be provided with an echogeniccoating that makes the needle more visible under ultrasound imaging. Forexample, in some embodiments, the entire length of the needle may beprovided with an echogenic coating. Alternatively, the one or more ofthe marks 815, 820, 825, may be provided with an echogenic coating suchthat the distal end, proximal end, or center of the cryozone associatedwith the needle is visible under ultrasound imaging. In otherembodiments, the one or more marks may be provided by a lack ofechogenic coating. For example, in some embodiments, the length of theneedle may be provided with an echogenic coating except for at the oneor more marks 815, 820, 825, such that when viewed under ultrasoundguidance, the distal, proximal, or center of the cryozone would beassociated with the portion of the needle without the echogenic coating.Alternatively, the length of the needle may be provided with theechogenic coating that ceases at the center of the associated cryozone,such that when viewed under ultrasound guidance, the distal end of theechogenic coating would be associated with a center of a cryozone of theneedle.

Long needles may be used in some embodiments (e.g., 8-15 mm, 20 mm, 90mm etc.). Longer needles may require a smaller gauge (larger diameter)needle so they have sufficient rigidity to maintain consistent spacingwhen placed deep in the tissue, but not so large as to createsignificant mechanical injury to the skin and tissue when inserted(e.g., greater than 20 ga). Alternate configurations of the device mayhave two or more needles spaced generally 3-5 mm apart of lengthsranging from up to 20 mm or greater, typically of 25 gauge or 23 gauge.Single needle configurations may be even longer (e.g., 90 mm) forreaching target tissues that are even deeper (e.g., >15 mm or so belowthe dermis). Longer needle devices (e.g., >10 mm) may not need activeheating of the skin warmer and/or cladding found in designs usingshorter needle(s) as the cooling zone may be placed sufficiently deepbelow the dermis to prevent injury. In some embodiments, devices withsingle long needle configurations may benefit from active nerve locationsuch as ultrasound or electrical nerve stimulation to guide placement ofthe needle. Further, larger targets may require treatment from bothsides to make sure that the cold zone created by the needle fully coversthe target. Adjacent treatments placing the needle to either side of anerve during two successive treatment cycles may still provide aneffective treatment of the entire nerve cross-section.

In some situations, a probe with multiple spaced apart needles may bepreferable (e.g., 2, 3, 4 or more). A device employing multiple needlesmay decrease the total treatment duration by creating larger coolingzones. Further, a multi-needle device may be configured to providecontinuous cooling zones between the spaced apart needles. In someembodiments, the needles may be spaced apart by 1-5 mm. The spacing maybe dependent on the type of tissue being targeted. For example, whentargeting a nerve, it may be preferable to position the nerve betweenthe two or more needles so that cooling zones are generated on bothsides of the nerve. Treating the nerve from both sides may increase theprobability that the entire cross-section of the nerve will be treated.For superficial peripheral nerves, the nerves may be at depths rangingfrom 2-6 mm and may be smaller in diameter, typically <2 mm.Accordingly, devices for treating superficial peripheral nerves maycomprises two or more 27 gauge needles spaced <2 mm apart and havingtypical lengths less than 7 mm (e.g., 6.9 mm); however longer needlesmay be required to treat the full patient population in order to accesspatients with altered nerve anatomy or patients with higher amounts ofsubcutaneous tissue such as those with high BMIs.

A treatment cycle may comprise a 10 second pre-warm phase, followed by a60 second cooling phase, followed thereafter by a 15 second post-warmphase with 40° C. skin warmer throughout. It should be understood thatother treatment cycles may be implemented. In some embodiments, apre-warming cycle can range from 0 to up to 30 seconds, preferably 5-15seconds sufficient to pre-warm the cryoprobe and opposing skin.Treatment cooling may range from 5-120 seconds, preferably 15-60 secondsbased on the flow rate, geometry of the cryoprobe, size of the therapyzone, size of the target nerve or tissue and the mechanism of actiondesired. Post-warming can range from 0-60 seconds, preferably 10-15seconds sufficient to return the cryoprobe to a steady state thermalcondition and possibly to free the cryoprobe needle(s) from the frozentherapy zone (e.g., at least 0° C.) prior to removing the cryoprobeneedles. For example, in some embodiments, devices with 6.9 mm longcladded needles may be warmed with a 30° C. heater. The treatment cyclemay comprise a 10 second pre-warm phase, a 35 second cooling phase, anda 15 second post-warm phase. Advantageously, such a treatment cycle maymake an equivalent cryozone as the treatment cycle used in the study ina shorter amount of time (e.g., a 35 second cooling phase compared to a60 second cooling phase).

In some embodiments, treatment devices and treatment cycles may beconfigured to deliver a preferred cryozone volume. For example, in someembodiments, devices and treatment cycles may be configured to generatecryozones (defined by the 0° C. isotherm) having a cross-sectional areaof approximately 14-55 mm2 (e.g., 27 mm2). Optionally, the devices andtreatment cycles may be configured to generate cryozones having a volumeof approximately 65-125 mm3 (e.g., 85 mm3).

Accordingly, in some embodiments, treatment cycles may be configuredwith cooling phases ranging between 15-75 seconds (e.g., 30 seconds, 35seconds, 40 seconds, 45 seconds, etc.) depending on cooling fluid flowrates, warming phase durations, warming phase temperature, number ofcooling needles, needle spacing, or the like in order to generate adesired cryozone. Similarly, treatment cycles may be configured withwarming phases operating a temperature ranging between 10-45° C.depending on the length of cooling phases, number of needles, needlespacing, etc. in order to generate a desired cryozone. Generally, withhigher degree warming phases, the duration of the pre-warm phase and thecooling phase will be longer, however the post-warm phase duration maybe reduced. In some embodiments the temperature can be set to onetemperature during the pre-warm phase, another temperature during thecooling phase, and a third temperature during the post-warm phase.

In some embodiments, devices may be configured to limit flow rate of acooling fluid to approximately 0.34-0.80 SLPM (gas phase). Optionally,in some embodiments, it may be preferable to configure the device andthe treatment cycle to maintain the tip a less than −55° C. duringcooling phases. In some embodiments, it may be preferable to configurethe device and the treatment cycle to have the tip return to at least 0°C. at the end of the post-warm phase so as to ensure the device may besafely removed from the tissue after the treatment cycle.

While generally describing treatment cycles as includingpre-heating/warming phases, it should be understood that other treatmentcycles may not require a pre-heating/warming phase. For example, largerneedle devices (e.g., 30-90 mm) may not require a pre-heat/warm phase.Larger needles may rely on the body's natural heat to bring the needleto a desired temperature prior to a cooling phase.

In some embodiments of the present invention, treatment guidance canrely on rigid or boney landmarks because they are less dependent uponnatural variations in body size or type, e.g., BMI. Soft tissues,vasculature and peripheral nerves pass adjacent to the rigid landmarksbecause they require protection and support. The target nerve to relievepain can be identified based on the diagnosis along with patientsidentifying the area of pain, biomechanical movements that evoke painfrom specific areas, palpation, and diagnostic nerve blocks using atemporary analgesic (e.g., 1-2% Lidocaine). Target nerve (tissue) can belocated by relying on anatomical landmarks to indicate the anatomicalarea through which the target nerve (tissue) reside. Alternatively,nerve or tissue locating technologies can be used. In the case ofperipheral nerves, electrical stimulation or ultrasound can be used tolocate target nerves for treatment. Electrical nerve stimulation canidentify the nerve upon stimulation and either innervated muscle twitchin the case of a motor nerve or altered sensation in a specific area inthe case of a sensory nerve. Ultrasound is used to visualize the nerveand structures closely associated with the nerve (e.g., vessels) toassist in placing the cryoprobe in close proximity to the target nerve.By positioning the patient's skeletal structure in a predeterminedposition (e.g., knee bent 30 degrees or fully extended), one canreliably position the bones, ligaments, cartilage, muscle, soft tissues(including fascia), vasculature, and peripheral nerves. Externalpalpation can then be used to locate the skeletal structure and therebylocate the pathway and relative depth of a peripheral nerve targeted fortreatment.

A treatment of peripheral nerve tissue to at least −20° C. for greaterthan 10 seconds (e.g., at least 20 seconds preferably) may be sufficientto trigger 2nd degree Wallerian degeneration of the axon and myelinatedsheath. Conduction along the nerve fibers is stopped immediatelyfollowing treatment. This provides immediate feedback as to the locationof the target peripheral nerve or associated branches when theassociated motion or sensation is modified. This can be used to refinerigid landmark guidance of future treatments or to determine whetheraddition treatment is warranted.

By using rigid landmarks, one may be able to direct the treatmentpattern to specific anatomical sites where the peripheral nerve islocated with the highest likelihood. Feedback from the patientimmediately after each treatment may verify the location of the targetperipheral nerve and its associated branches. Thus, it should beunderstood that in some embodiments, the use of an electrical nervestimulation device to discover nerve location is not needed or used,since well-developed treatment zones can locate target nerves. This maybe advantageous, due the cost and complexity of electrical nervestimulation devices, which are also not always readily available.

In alternative embodiments of the invention, one could use an electricalnerve stimulation device (either transcutaneous or percutaneous) tostimulate the target peripheral nerve and its branches. Withtranscutaneous electrical nerve stimulation (TENS) the pathway of thenerve branch can be mapped in XY-coordinates coincident with the skinsurface. The Z-coordinate corresponding to depth normal to the skinsurface can be inferred by the sensitivity setting of the electricalstimulation unit. For example, a setting of 3.25 mA and pulse durationof 0.1 ms may reliably stimulate the frontal branch of the temporalnerve when it is within 7 mm of the skin surface. If a higher currentsetting or longer pulse duration is required to stimulate the nerve,then the depth may be >7 mm. A percutaneous electrical nerve stimulator(PENS) can also be used to locate a target peripheral nerve. Based onrigid anatomical landmarks, a PENS needle can be introduced through thedermis and advanced into the soft tissues. Periodic stimulating pulsesat a rate of 1-3 Hz may be used to stimulate nerves within a knowndistance from the PENS needle. When the target nerve is stimulated, thesensitivity of the PENS can be reduced (e.g., lowering the currentsetting or pulse duration) narrowing the range of stimulation. When thenerve is stimulated again, now within a smaller distance, the PENSsensitivity can be reduced further until the nerve stimulation distanceis within the therapy zone dimensions. At this point, the PENS needlecan be replaced with the focused cold therapy needle(s) and a treatmentcan be delivered. The PENS and focused cold therapy needles can beintroduced by themselves or through a second larger gage needle orcannula. This may provide a rigid and reproducible path when introducinga needle and when replacing one needle instrument with another. A rigidpathway may guide the needle to the same location by preventing needletip deflection, which could lead to a misplaced therapy and lack ofefficacy.

While many of the examples disclosed herein related to puncturing theskin in a transverse manner to arrive at a target nerve, othertechniques can be used to guide a device to a target nerve. For example,insertion of devices can be made parallel to the surface of the skin,such that the (blunted) tip of the device glides along a particularfascia to arrive at a target sensory nerve. Such techniques and devicesare disclosed in U.S. Pub. No. 2012/0089211, the entirety of which isincorporated by reference. Possible advantages may include a singleinsertion site, and guidance of a blunt tip along a layer common withthe path or depth of the target nerve. This technique may be aposition-treatment-thaw, reposition-treatment-thaw, etc.

In further aspects of the present invention, a focused cold therapytreatment device may be provided that is adapted to couple with or befully integrated with a nerve stimulation device such that nervestimulation and focused cold therapy may be performed concurrently withthe cryo-stimulation device. Accordingly, embodiments of the presentdisclosure may improve nerve targeting during FCT procedures.Improvements in nerve localization and targeting may increase treatmentaccuracy and physician confidence in needle placement during treatment.In turn, such improvements may decrease overall treatment times, thenumber of repeat treatments, and the re-treatment rate. Further,additional improvements in nerve localization and targeting may reducethe number of applied treatment cycles and may also reduce the number ofcartridge changes (when replaceable refrigerant cartridges are used).Thus, embodiments of the present disclosure may provide one or moreadvantages for FCT by improving localization and treatment of targetnerves. Hence, some aspects of the present disclosure provide methods,devices, and systems for localizing and targeting a nerve with focusedcold therapy.

FIG. 17 illustrates one such method 500 of locating and treating a nerveaccording to some embodiments. At step 502, a transcutaneous electricalstimulation (TENS) device and/or anatomical landmarks may be used topre-locate a target nerve or otherwise generally locate a target nervelocation. At step 504, one or more needles of an integrated cooling andstimulation device may be inserted into the tissue. At step 506,percutaneous nerve localization may be conducted to determine 507whether the one or more needles is proximal to the target nerve. If thenerve localization using percutaneous nerve stimulation 506 isunsuccessful, the one or more needles may be repositioned 508 within thetissue. Thereafter, percutaneous nerve localization 506 may be conductedagain to determine whether the repositioning successfully places the oneor more needles sufficiently proximal to the target nerve. If the nervelocalization using percutaneous nerve stimulation is successful uponinsertion 504 or after repositioning 508, the focused cold therapy maythen be delivered 509 using one or more needles of the treatment device.

The method 500 may be used for cosmetic and/or other medical treatments(e.g., pain alleviation or the like). In some cosmetic applications, atarget nerve may be between 3-7 mm in depth, for example. In othermedical applications, a target nerve may be upwards of 50 mm in depth ordeeper. It may be beneficial to locate the target nerve to within 2 mmfor at least some of treatments. Additionally, in some applications, itmay be beneficial to be able to locate and differentiate motor nervesfrom sensory nerves. For example, in some cosmetic applications thattarget motor nerves for wrinkle alleviation, it may be advantageous tolocate and avoid treating sensory nerves to limit side effects due tothe cosmetic procedure. For example, method 500 may be used to targetthe temporal branch of the facial nerve (TBFN). The nerve may run alongthe Pitanguy line at a depth of 0.5 mm above the SDTF layer. The depthof the SDTF layer varies along treatment lines and among individuals andas such the target nerve depth may also vary from patient to patient.Accordingly, an integrated stimulation and cooling treatment device maybe beneficial in such a procedure. In an additional non-limitingexample, method 500 may be used to target the infrapatellar branch ofthe saphenous nerve (ISN). The ISN is a sensory nerve that innervatesthe anterior aspect of the knee. Focused Cold Therapy of the ISN mayalleviate pain experienced in the knee of a patient (e.g., due toosteoarthritis or the like). While anatomical features may be used togenerally localize a treatment box for the target nerve, a plurality oftreatments may be needed before the target nerve is treated within thebox. Accordingly, an integrated nerve stimulation and cooling treatmentdevice may provide more accurate treatments and may thereby limit thenumber of treatments required for treatment and reduce a treatment time.Additional treatments that may benefit from such a device include, butare not limited to: head pain, knee pain, plantar fasciitis, back pain,tendonitis, shoulder pain, movement disorders, intercostal pain,post-herpetic neuralgia, post-surgical pain, phantom limb pain, etc.

Electrical nerve stimulation localizes nerves by transmission ofelectrical pulses. The electrical impulses in turn excite nerves byinducing a flow of ions through the neuronal cell membrane(depolarization), which results in an action potential that maypropagate bi-directionally. The nerve membrane depolarization may resultin either muscle contraction or paresthesia, depending on the type ofnerve fiber (motor vs. sensory). The current density a nerve reacts toor “sees” decreases with distance from the nerve:

$I = {k( \frac{i}{r^{2}} )}$

where k is a constant that depends on electrode size, pulse width,tissue impedance, nerve fiber size, etc.; i is the current delivered;and r is the distance from the nerve. This corresponds to higherthreshold currents at a distance from the nerve.

In some embodiments, an insulated needle having a small conducting oruninsulated portion may have minimal current threshold when the needleis on the nerve. Non-insulated needles in contrast may transmit currentthrough the entire length and may have a lower current density along thetreatment portion of the needle. As such, non-insulated needles mayrequire more current than insulated needles at the same distance fromthe nerve and may have less discrimination of distances as the needleapproaches the nerve. Accordingly, while not essential, in someembodiments, cryo-stimulation devices may be provided that include aninsulated nerve stimulation needle.

In some embodiments, the integrated cooling and stimulation needle probemay have a single needle for both cooling and nerve stimulation. Forexample, FIG. 18A illustrates an exemplary needle assembly 510 having asingle needle 512 that may be used to perform the method 500 accordingto some embodiments of the disclosure. FIG. 18B illustrates a close upview of the needle 512 of the exemplary needle assembly 510 of FIG. 18Aaccording to some embodiments. In use, coolant may flow through theneedle 512 (e.g. via cooling fluid supply tube or the like) therebycooling a distal end of the needle 512 and producing a cold zone 521associated with the needle 512. The needle 512 may have a cooling center522 along the length of the needle 512 that is associated with a centerof the cold zone 521 produced by the needle 512. Additionally, theneedle 512 may be constructed from an electrically conductive materialand may also have an electrically insulated coating 523 disposed about alength of the needle 512. The electrically insulated coating 523 mayelectrically insulate a proximal portion of a length of the needle 512that is adjacent the distal end of the housing 514 and may extend towarda distal portion of the length of the needle 512. The electricallyinsulated coating 523 may be a fluoropolymer coating, a silicone rubbercoating, a parylene coating, a ceramic coating, an epoxy coating, apolyimide coating or the like. A proximal end of needle 512 may beuninsulated and may be configured to couple with an electrical nervestimulation generator 524 of a percutaneous electrical stimulationdevice. A distal end of needle 512 may be uninsulated such that anelectrical field 526 (FIG. 18B) generated by electrical nervestimulation generator 524 happens about the distal end of needle 512. Insome embodiments, the distal end of the electrically insulated coating523 may be at the cooling center 522 of the needle 512. In suchembodiments, the intensity of the electrical field 526 produced byelectrical nerve stimulation generator 524 may be co-incident with thecenter of the cold zone 521 that is produced by the needle 512, asillustrated in FIG. 18B.

In some embodiments the coating 523 may be 0.00125 inches thick.Optionally, coating 523 may be applied by masking off the cooling center522 of needle 512 and then coating the needle 512 with the electricallyinsulating material 523. Additionally, while needle assembly 510 isillustrated with a needle 512 without insulation at the distal end ofthe needle 512, it should be understood that this is exemplary. In someembodiments of the present disclosure, the distal end of needle 512 mayhave a coating of the electrically insulating material 523, asillustrated in FIG. 18C, while the portion of the needle 512 associatedwith the center of the cold zone 521 remains uninsulated.

As mentioned above, a proximal end of needle 512 may be uninsulated andmay be configured to couple with an electrical nerve stimulationgenerator 524. In some embodiments, the electrical nerve stimulationgenerator 524 may have an input that is configured to couple with acorresponding electrical port of the treatment device. For example, FIG.19 illustrates an exemplary treatment device 600. The treatment device600 includes a handle 610 that is configured to be coupled with areplaceable needle assembly 612. The handle 610 may further include areplaceable refrigerant cartridge 614. The cartridge 614 may be securedto handle 610 by a cartridge cap 616. The cartridge 614 and thecartridge cap 616 may be housed by distal cover 618. Optionally, aneedle assembly cover 620 may be provided to house the needle assembly612 when the device 600 is not in use.

In some embodiments, the input electrical port configured to receive aninput from the electrical nerve stimulation generator 524 may beprovided on the replaceable needle assembly 612. For example, asillustrated in FIG. 20 illustrates an exemplary needle assembly 612 withan input electrical port 622. The input electrical port 622 isconfigured to couple with electrical nerve stimulation generator 524 toelectrically couple the electrical nerve stimulation generator 524 withthe uninsulated proximal portion of one or more electrical stimulationneedles 623 of device 600.

Additionally, in some embodiments, the input electrical port configuredto receive an input from the electrical nerve stimulation generator 524may be provided on the handle 610 in addition to or in the alternativeto the electrical port 622 on needle assembly 612. For example, asillustrated in FIG. 21, a proximal end of handle 610 may includeelectrical port 624 for receiving an input from the electrical nervestimulation generator 524. FIG. 22 illustrates a close up view of theproximal end of housing 610. As can be seen, the distal end of housing610 may include a status light 626 for the cartridge status, a statuslight 628 for the needle assembly, a device serial number 630, and/or areset access 632 in addition to electrical port 624. The one or moreinput electrical ports 622, 624 may be configured to be electricallycoupled with one or more of the electrical stimulation needles of thedevice 600.

Optionally, in some embodiments, the electrical nerve stimulationgenerator 524 may be fully integrated with the treatment device. Forexample, FIG. 23 illustrates yet another exemplary treatment system 634with a fully integrated electrical nerve stimulation generator 524. Thesystem 634 includes a housing 636 that defines a handle of the device.An electrical adapter 638 may be disposed at the distal end of housing636 that is configured to electrically couple with a replaceable needleassembly (not shown). Housing 636 may house electrical nerve stimulationgenerator 524. Electrical nerve stimulation generator 524 mayelectrically couple with the adapter 638. Adapter 638 may provide aninterface between the electrical nerve stimulation generator 524 and areplaceable needle assembly when the needle assembly is coupled withadapter 638.

While the exemplary needle assembly 510 of FIG. 18A is illustrated witha single needle for performing the cooling treatment in addition to thenerve stimulation, it should be understood that other treatment devicesor needle assemblies may be provided with a plurality of needles. One ofskill in the art will appreciate that two, three, four, five, six, ormore needles may be used. When a plurality of needles are used, they maybe arranged in any number of patterns. For example, a single lineararray may be used, or a two dimensional or three dimensional array maybe used. Examples of two dimensional arrays include any number of rowsand columns of needles (e.g. a rectangular array, a square array,elliptical, circular, triangular, etc.), and examples of threedimensional arrays include those where the needle tips are at differentdistances from the probe hub, such as in an inverted pyramid shape.Accordingly, in some embodiments, the integrated cooling and stimulationneedle probe may have a plurality of needles for cooling and/or nervestimulation. For example, FIG. 24 illustrates an exemplary needleassembly 710 that includes a plurality of needles 712 that may performthe method 500 with a plurality of needles according to some embodimentsof the disclosure. In use, coolant may flow through one or more of theneedles 712 thereby cooling a distal end of the one or more needles 712and producing a cold zone 721 associated with the needle assembly 710.The needle assembly 710 may have a cooling center 722 that is associatedwith a center of the cold zone 721 produced by the one or more needles712. Additionally, at least one of the needles 712 (in the illustratedembodiment, center needle 712 c) may be constructed from an electricallyconductive material and may also have an electrically insulated coating723 disposed about a length of the needle 712 c. The electricallyinsulated coating 723 may electrically insulate a proximal portion of alength of the needle 712 c that is adjacent the distal end of thehousing 714 and may extend toward a distal portion of the length of theneedle 712 c. The electrically insulated coating 723 may be afluoropolymer coating, a silicone rubber coating, a parylene coating, aceramic coating, an epoxy coating, a polyimide coating or the like. Aproximal end of needle 712 c may be uninsulated and may be configured tocouple with the electrical nerve stimulation generator 524 of apercutaneous electrical stimulation device, e.g., through a mannerdescribed above, such as an electrical port on the needle assemblyhousing, an electrical port on the treatment device housing, anintegrated generator 524 that electrically couples to needle 712 c viaan adapter between the device handle and the needle assembly 710 or thelike. The portion of needle 712 c that is disposed at the cooling center722 may be uninsulated such that the intensity of the electrical fieldproduced by electrical nerve stimulation generator 524 via needle 712 cmay be co-incident with the center of the cold zone 721 that is producedby the needle assembly 710.

While illustrated as including three needles 712, it should beunderstood that this is exemplary and non-limiting. Two, four, five ormore needles may be provided in other embodiments. Further, whileillustrated with each of the needles 712 being supplied by a coolingfluid supply tube and thus each of the needles 712 being configured tocool to produce cold zone 721, in other embodiments, only some of theplurality of needles may be configured to provide the cooling treatment.Other needles 712 may be provided separately for electrical stimulation.Accordingly, in some embodiments, center needle 712 may be provided forelectrical stimulation only, while the adjacent needles 712 may beprovided to produce cold zone 721. Put in another way, in someembodiments, stimulation needle (e.g., needle 712 c) may not include acold center along the length of the needle, but nevertheless, thecooling center 722 of the cold zone 721 associated with the needleassembly 710 may be disposed along the length of the stimulation needle.Thus, the stimulation needle may provide more accurate targeting of atarget nerve with the cold zone 721 whether or not it provides coolingitself.

Additionally, it should be understood that while assembly 710 isillustrated with a single stimulating needle 712 c, additional needles712 of assembly 710 may be configured to separately stimulate asdesired. Accordingly, some or all of the plurality of needles 712 may beconfigured to provide nerve stimulation. Thus, nerve stimulationgenerator 524 may be electrically coupled with each stimulating needle.

Further, in some embodiments, an adjacent needle (e.g., needles 712adjacent to 712 c) may provide an electrical ground during nervestimulation. Accordingly, one or more of the adjacent needles may beconstructed from a conductive material and may be uninsulated at alocation proximate to an uninsulated portion of an adjacent nervestimulation needle. Optionally, adjacent needles may also include anelectrically insulated coating that extends from a proximal portion ofthe needle adjacent to the housing toward a distal portion of theneedle.

In still further embodiments, during focused cold therapy delivery 509,nerve stimulation may be conducted to provide feedback to the treatment.For example, in some embodiments, nerve stimulation may be performedcontinuously concurrently with the focused cold therapy delivery 509 todetermine the efficacy of the treatment in real time. Optionally, thenerve stimulation may be repeated in a discrete intervals during focusedcold therapy delivery 509. In such embodiments, the focused cold therapydelivery 509 may continue until there is a cessation of motor functionor paresthesia. In some embodiments, the focused cold therapy 509 may beshorter in duration when the nerve stimulation feedback is associatedwith a successful treatment. In other embodiments, the focused coldtherapy 509 may be longer in duration when the nerve stimulationfeedback indicates that the nerve has not been successfully treated.Further, initial tests surprisingly suggest that ice ball formation bythe treatment needles of the assembly may be produced at a quicker ratewhen the electrical stimulation is concurrently delivered.

In still further embodiments of the present disclosure, a focused coldtherapy treatment device may be provided with an integratedtranscutaneous electrical stimulation device. For example, FIG. 25illustrates an exemplary treatment system 750 with an integratedtranscutaneous electrical stimulation probe 752 according to someembodiments. FIG. 26 illustrates an exemplary operation of the system750 of FIG. 25 according to some embodiments. Treatment system 750further includes two cooling treatment needles 754 for insertion throughthe tissue surface 756 to produce a cooling zone 758 to treat targetnerve 760. The transcutaneous electrical stimulation probe 752 may havedistal end for providing electrical stimulation through the tissuesurface 756 for localizing the target nerve 760. A proximal portion ofprobe 752 may be coupled with a spring 762. After identifying a locationof the target nerve 760, the device 750 may be pressed distally againstthe tissue surface 756 to insert needles 754 into the tissue. Duringneedle 754 insertion, the spring 762 may compress and the probe 752 maywithdraw into the housing of treatment system 750. Thereafter, theneedles 754 may deliver the focused cold therapy to produce cold zone758. Such an embodiment may localize a target nerve transcutaneously andmay allow the treatment needles to be inserted into the tissue withouthaving to first interchange the transcutaneous electrical stimulationdevice for the device with the cooling treatment needles.

One or more computing devices may be adapted to provide desiredfunctionality by accessing software instructions rendered in acomputer-readable form. When software is used, any suitable programming,scripting, or other type of language or combinations of languages may beused to implement the teachings contained herein. However, software neednot be used exclusively, or at all. For example, some embodiments of themethods and systems set forth herein may also be implemented byhard-wired logic or other circuitry, including but not limited toapplication-specific circuits. Combinations of computer-executedsoftware and hard-wired logic or other circuitry may be suitable aswell.

Embodiments of the methods disclosed herein may be executed by one ormore suitable computing devices. Such system(s) may comprise one or morecomputing devices adapted to perform one or more embodiments of themethods disclosed herein. As noted above, such devices may access one ormore computer-readable media that embody computer-readable instructionswhich, when executed by at least one computer, cause the at least onecomputer to implement one or more embodiments of the methods of thepresent subject matter. Additionally or alternatively, the computingdevice(s) may comprise circuitry that renders the device(s) operative toimplement one or more of the methods of the present subject matter.

Any suitable computer-readable medium or media may be used to implementor practice the presently-disclosed subject matter, including but notlimited to, diskettes, drives, and other magnetic-based storage media,optical storage media, including disks (e.g., CD-ROMS, DVD-ROMS,variants thereof, etc.), flash, RAM, ROM, and other memory devices, andthe like.

The subject matter of embodiments of the present invention is describedhere with specificity, but this description is not necessarily intendedto limit the scope of the claims. The claimed subject matter may beembodied in other ways, may include different elements or steps, and maybe used in conjunction with other existing or future technologies. Thisdescription should not be interpreted as implying any particular orderor arrangement among or between various steps or elements except whenthe order of individual steps or arrangement of elements is explicitlydescribed.

Different arrangements of the components depicted in the drawings ordescribed above, as well as components and steps not shown or describedare possible. Similarly, some features and sub-combinations are usefuland may be employed without reference to other features andsub-combinations. Embodiments of the invention have been described forillustrative and not restrictive purposes, and alternative embodimentswill become apparent to readers of this patent. Accordingly, the presentinvention is not limited to the embodiments described above or depictedin the drawings, and various embodiments and modifications may be madewithout departing from the scope of the claims below.

1. (canceled)
 2. A cryo-stimulation treatment device, comprising: aneedle having a proximal end and a distal end and a length therebetween,the needle configured to produce a cold zone for focused cold therapy,the needle having a cooling center along the length of the needle thatis associated with a center of the cold zone produced by the needle; anelectrically insulated coating disposed about the length of the needle,wherein the needle is electrically conductive and wherein the proximalend of the needle is configured to couple with an electrical nervestimulation generator that generates an electrical field about thedistal end of the needle for electrically stimulating and locating thetarget nerve; wherein the cooling center of the needle is uninsulatedsuch that an intensity of the electrical field is co-incident with thecenter of the cold zone produced by the needle; and a handle defined bya housing, and wherein the housing incorporates an electrical port thatelectrically couples with an uninsulated portion of the proximal end ofthe needle, the electrical port configured to receive an inputassociated with the electrical nerve stimulation generator to releasablyelectrically couple the electrical nerve stimulation generator and theneedle.
 3. The treatment device of claim 2, wherein the needle is partof a replaceable needle assembly configured for releaseable attachmentto the handle.
 4. The treatment device of claim 2, wherein theelectrically insulated coating comprises a fluoropolymer coating.
 5. Thetreatment device of claim 2, wherein the electrically insulated coatingcomprises a silicone rubber coating.
 6. The treatment device of claim 2,wherein the electrically insulated coating comprises a polyimidecoating.
 7. The treatment device of claim 2, wherein the electricallyinsulated coating comprises a parylene coating.
 8. The treatment deviceof claim 2, wherein the electrically insulated coating comprises anepoxy coating.
 9. The treatment device of claim 2, wherein theelectrically insulated coating comprises a ceramic coating.
 10. Thetreatment device of claim 2, wherein the needle is a first needle of aneedle assembly having the first needle and a second needle adjacent thefirst needle, and wherein the second needle acts as an electrical groundduring electrical stimulation of the nerve by the first needle.
 11. Acryo-stimulation treatment device, comprising: a needle assembly having:one or more treatment needles configured to produce a cold zone forfocused cold therapy of a target nerve; one or more stimulation needlesconstructed of electrically conductive material and being configured tocouple with an electrical nerve stimulation generator to produce anelectrical field for stimulating the target nerve; an electricallyinsulating coating on the one or more stimulation needles, wherein theone or more stimulation needles are uninsulated at a location of the oneor more stimulation needles that is coincident with a center of the coldzone produced by the one or more treatment needles; and a handle definedby a housing, and wherein the housing incorporates an electrical portthat electrically couples with an uninsulated portion of the one or morestimulation needles, the electrical port configured to receive an inputassociated with the electrical nerve stimulation generator to releasablyelectrically couple the electrical nerve stimulation generator and theone or more stimulation needles.
 12. The treatment device of claim 11,wherein the needle assembly is part of a replaceable needle assemblyconfigured for releaseable attachment to the handle.
 13. The treatmentdevice of claim 11, wherein the one or more stimulation needlescomprises a center needle and wherein the one or more treatment needlescomprises at least two needles that are adjacent the center needle andon opposite sides of the center needle.
 14. The treatment device ofclaim 11, wherein the one or more treatment needles comprises anelectrically insulating coating and wherein at least a distal portion ofthe one or more treatment needles is uninsulated and acts as anelectrical ground during electrical stimulation of the target nerve bythe one or more stimulation needles.
 15. The treatment device of claim11, wherein the one or more treatment needles are also stimulationneedles constructed of electrically conductive material and beingconfigured to couple with the electrical nerve stimulation generator toproduce an electrical field for stimulating the target nerve.
 16. Thetreatment device of claim 11, wherein the electrically insulated coatingcomprises a fluoropolymer coating.
 17. The treatment device of claim 11,wherein the electrically insulated coating comprises a silicone rubbercoating.
 18. The treatment device of claim 11, wherein the electricallyinsulated coating comprises a polyimide coating.
 19. The treatmentdevice of claim 11, wherein the electrically insulated coating comprisesa parylene coating.
 20. The treatment device of claim 11, wherein theelectrically insulated coating comprises an epoxy coating.
 21. Thetreatment device of claim 11, wherein the electrically insulated coatingcomprises a ceramic coating.